The skin is a complex structure that functions as a barrier to ingress of foreign substances into the body. Molecules moving from the environment into and through an intact skin must first penetrate the stratum corneum, which acts as highly resistant lipid barrier to penetration of these molecules into the skin. Significant efforts have been put forth in attempts to overcome the barrier of the stratum corneum in order to deliver topically functional agents into the skin.
Iontophoresis is in wide use in the administration of drugs. It effectively delivers an ionic form of a drug through the skin in the presence of an electrical potential. As iontophoresis avoids the gastrointestinal side effects sometimes associated with orally ingested or parenterally administered drugs and because of its non-invasive nature, iontophoresis is preferable to oral administration or to subcutaneous, intramuscular or intravenous injection.
Typically iontophoresis is performed by placing an electrode containing an ionic drug solution in contact with the skin at a location where the drug is to be transported. A second electrode is placed on the skin near the first electrode, and voltage is applied so as to cause current to pass through the skin, thereby completing the electrical circuit between the electrodes. As current flows, the ionic drug molecules migrate through the skin under the influence of the second electrode. One general class of electrode designs involves the use of a conductive element associated with a compartment or pouch into which a drug solution is introduced. One wall of the pouch typically comprises a permeable barrier, which serves to contain the solution, but permits drug ions to pass there through. Examples of such electrodes can be seen in U.S. Pat. Nos. 4,250,878, 4,419,092, and 4,477,971, among others.
A second class of electrode designs involves the use of a conductive element associated with a gel material for containing ionized drug without the use of a pouch. Examples of such bioelectrodes are found in U.S. Pat. Nos. 4,383,529, 4,474,570, and 4,747,819. Typically, these gel-type electrodes incorporate ionized drug into the gel at the time of manufacture.
A third type of electrode designs generally utilizes a conductive element associated with a hydratable element. The hydratable element is typically formed of a stack of sheets of a dry cross-linked hydrogel such as cross-linked polyethylene oxide (PEO). U.S. Pat. Nos. 6,169,920 and 6,317,629 assigned to Alza disclose iontophoretic drug delivery devices. U.S. Pat. Nos. 5,087,242, 5,374,241, 5,730,716, 6,731,977 assigned to Iomed disclose electrodes and devices for iontophoretic delivery of agents. U.S. Pat. No. 5,681,580 assigned to Samsung Electro-Mechanics Co. discloses a patch-type device for iontophoretic transdermal medication of insulin. A different type of transdermal delivery device is disclosed in U.S. Pat. No. 6,148,232 to Avrahami. The device includes a plurality of electrodes, which are applied at respective points on skin of a subject, and a power source that applies electrical energy between two or more of the electrodes to cause ablation of the stratum corneum, primarily beneath the respective electrodes, and to generate micro-channels. Various techniques for limiting ablation to the stratum corneum are described, including spacing of the electrodes and monitoring the electrical resistance of skin between adjacent electrodes. Sintov et al. (J. Controlled Release 89: 311-320, 2003) and U.S. Pat. Nos. 6,597,946; 6,611,706; 6,708,060; and 6,711,435 to Avrahami disclose improvements and additional devices for ablating the stratum corneum and generating micro-channels so as to facilitate transdermal passage of substances through the skin. The devices are aimed at reducing sensation and minimizing damage to skin underlying the stratum corneum during micro-channel generation.
International PCT Applications Publication Nos. WO 2004/039426; WO 2004/039427WO 2004/039428; WO2004/112689; WO2005/056075 and WO2005/069736, all assigned to the applicant of the present invention, disclose systems and methods for transdermal delivery of pharmaceutical and cosmetic agents. Specifically disclosed are systems and methods for transdermal delivery of hydrophilic anti-emetic agents, dried or lyophilized polypeptide compositions, water-insoluble drugs and polynucleotides.
There is still a recognized need for, and it would be highly advantageous to have, efficient methods for transdermal delivery of pharmaceutical agents generally and polypeptides in particular, which methods provide improved delivery and bioavailability over that of the known methods.